Hyaluronan and proteoglycan link protein 1(Hapln1)supports active cardiomyogenesis in zebrafish hearts,but its regulation in mammal cardiomyocytes is unclear.This study aimed to explore the potential regulation of Hap...Hyaluronan and proteoglycan link protein 1(Hapln1)supports active cardiomyogenesis in zebrafish hearts,but its regulation in mammal cardiomyocytes is unclear.This study aimed to explore the potential regulation of Hapln1 in the dedifferentiation and proliferation of cardiomyocytes and its therapeutic value in myocardial infarction with human induced pluripotent stem cell(hiPSC)-derived cardiomyocytes(CMs)and an adult mouse model of myocardial infarction.HiPSC-CMs and adult mice with myocardial infarction were used as in vitro and in vivo models,respectively.Previous single-cell RNA sequencing data were retrieved for bioinformatic exploration.The results showed that recombinant human Hapln1(rhHapln1)promotes the proliferation of hiPSC-CMs in a dose-dependent manner.As a physical binding protein of Hapln1,versican interacted with Nodal growth differentiation factor(NODAL)and growth differentiation factor 11(GDF11).GDF11,but not NODAL,was expressed by hiPSC-CMs.GDF11 expression was unaffected by rhHapln1 treatment.However,this molecule was required for rhHapln1-mediated activation of the transforming growth factor(TGF)-β/Drosophila mothers against decapentaplegic protein(SMAD)2/3 signaling in hiPSC-CMs,which stimulates cell dedifferentiation and proliferation.Recombinant mouse Hapln1(rmHapln1)could induce cardiac regeneration in the adult mouse model of myocardial infarction.In addition,rmHapln1 induced hiPSC-CM proliferation.In conclusion,Hapln1 can stimulate the dedifferentiation and proliferation of iPSC-derived cardiomyocytes by promoting versican-based GDF11 trapping and subsequent activation of the TGF-β/SMAD2/3 signaling pathway.Hapln1 might be an effective hiPSC-CM dedifferentiation and proliferation agent and a potential reagent for repairing damaged hearts.展开更多
Cardiac-resident macrophages(CRMs)play important roles in homeostasis,cardiac function,and remodeling.Although CRMs play critical roles in cardiac regeneration of neonatal mice,their roles are yet to be fully elucidat...Cardiac-resident macrophages(CRMs)play important roles in homeostasis,cardiac function,and remodeling.Although CRMs play critical roles in cardiac regeneration of neonatal mice,their roles are yet to be fully elucidated.Therefore,this study aimed to investigate the dynamic changes of CRMs during cardiac ontogeny and analyze the phenotypic and functional properties of CRMs in the promotion of cardiac regeneration.During mouse cardiac ontogeny,four CRM subsets exist successively:CX3CR1+CCR2-Ly6C-MHCII-(MP1),CX3CR1lowCCR2lowLy6C-MHCII-(MP2),CX3CR1-CCR2+Ly6C+MHCII-(MP3),and CX3CR1+CCR2-Ly6C-MHCII+(MP4).MP1 cluster has different derivations(yolk sac,fetal liver,and bone marrow)and multiple functions population.Embryonic and neonatal-derived-MP1 directly promoted cardiomyocyte proliferation through Jagged-1-Notch1 axis and significantly ameliorated cardiac injury following myocardial infarction.MP2/3 subsets could survive throughout adulthood.MP4,the main population in adult mouse hearts,contributed to inflammation.During ontogeny,MP1 can convert into MP4 triggered by changes in the cellular redox state.These findings delineate the evolutionary dynamics of CRMs under physiological conditions and found direct evidence that embryonic and neonatal-derived CRMs regulate cardiomyocyte proliferation.Our findings also shed light on cardiac repair following injury.展开更多
Heart regeneration occurs by dedifferentiation and proliferation of pre-existing cardiomyocytes(CMs).However,the signaling mechanisms by which injury induces CM renewal remain incompletely understood.Here,we find that...Heart regeneration occurs by dedifferentiation and proliferation of pre-existing cardiomyocytes(CMs).However,the signaling mechanisms by which injury induces CM renewal remain incompletely understood.Here,we find that cardiac injury in zebrafish induces expression of the secreted Wnt inhibitors,including Dickkopf 1(Dkkl),Dkk3,secreted Frizzled-related protein 1(sFrpl),and sFrp2,in cardiac tissue adjacent to injury sites.Experimental blocking of Wnt activity via Dkkl overexpression enhances CM proliferation and heart regeneration,whereas ectopic activation of Wnt8 signaling blunts injury-induced CM dedifferentiation and proliferation.Although Wnt signaling is dampened upon injury,the cytoplasmic β-catenin is unexpectedly increased at disarrayed CM sarcomeres in myocardial wound edges.Our analyses indicated that p21-activated kinase 2(Pak2)is induced at regenerating CMs,where it phosphorylates cytoplasmic β-catenin at Ser 675 and increases its stability at disassembled sarcomeres.Myocardial-specific induction of the phospho-mimeticβ-catenin(S675E)enhances CM dedifferentiation and sarcomere disassembly in response to injury.Conversely,inactivation of Pak2 kinase activity reduces the Ser 675-phosphorylatedβ-catenin(pS675-β-catenin)and attenuates CM sarcomere disorganization and dedifferentiation・Taken together,these findings demonstrate that coordination of Wnt signaling inhibition and Pak2/pS675-βYatenin signaling enhances zebrafish heart regeneration by supporting CM dedifferentiation and proliferation.展开更多
In the mammalian heart,cardiomyocytes are forced to withdraw from the cell cycle shortly after birth,limiting the ability of the heart to regenerate and repair.The development of multimodal regulation of cardiac proli...In the mammalian heart,cardiomyocytes are forced to withdraw from the cell cycle shortly after birth,limiting the ability of the heart to regenerate and repair.The development of multimodal regulation of cardiac proliferation has verified that pre-existing cardiomyocyte proliferation is an essential driver of cardiac renewal.With the continuous development of genetic lineage tracking technology,it has been revealed that cell cycle activity produces polyploid cardiomyocytes during the embryonic,juvenile,and adult stages of cardiogenesis,but newly formed mononucleated diploid cardiomyocytes also elevated sporadically during myocardial infarction.It implied that adult cardiomyocytes have a weak regenerative capacity under the condition of ischemia injury,which offers hope for the clinical treatment of myocardial infarction.However,the regeneration frequency and source of cardiomyocytes are still low,and the mechanism of regulating cardiomyocyte proliferation remains further explained.It is noteworthy to explore what force triggers endogenous cardiomyocyte proliferation and heart regeneration.Here,we focused on summarizing the recent research progress of emerging endogenous key modulators and crosstalk with other signaling pathways and furnished valuable insights into the internal mechanism of heart regeneration.In addition,myocardial transcription factors,non-coding RNAs,cyclins,and cell cycle-dependent kinases are involved in the multimodal regulation of pre-existing cardiomyocyte proliferation.Ultimately,awakening the myocardial proliferation endogenous modulator and regeneration pathways may be the final battlefield for the regenerative therapy of cardiovascular diseases.展开更多
The formation of new and functional cardiomyocytes requires a 3-step process:dedifferentiation,proliferation,and redifferentiation,but the critical genes required for efficient dedifferentiation,proliferation,and redi...The formation of new and functional cardiomyocytes requires a 3-step process:dedifferentiation,proliferation,and redifferentiation,but the critical genes required for efficient dedifferentiation,proliferation,and redifferentiation remain unknown.In our study,a circular trajectory using single-nucleus RNA sequencing of the pericentriolar material 1 positive(PCM1^(+))cardiomyocyte nuclei from hearts 1 and 3 days after surgery-induced myocardial infarction(MI)on postnatal Day 1 was reconstructed and demonstrated that actin remodeling contributed to the dedifferentiation,proliferation,and redifferentiation of cardiomyocytes after injury.We identified four top actin-remodeling regulators,namely Tmsb4x,Tmsb10,Dmd,and Ctnna3,which we collectively referred to as 2D2P.Transiently expressed changes of 2D2P,using a polycistronic non-integrating lentivirus driven by Tnnt2(cardiac-specific troponin T)promoters(Tnnt2-2D2P-NIL),efficiently induced transiently proliferative activation and actin remodeling in postnatal Day 7 cardiomyocytes and adult hearts.Furthermore,the intramyocardial delivery of Tnnt2-2D2P-NIL resulted in a sustained improvement in cardiac function without ventricular dilatation,thickened septum,or fatal arrhythmia for at least 4 months.In conclusion,this study highlights the importance of actin remodeling in cardiac regeneration and provides a foundation for new gene-cocktail-therapy approaches to improve cardiac repair and treat heart failure using a novel transient and cardiomyocyte-specific viral construct.展开更多
Heart regeneration is a fascinating and complex biological process. Decades of intensive studies have revealed asophisticated molecular network regulating cardiac regeneration in the zebrafish and neonatal mouse heart...Heart regeneration is a fascinating and complex biological process. Decades of intensive studies have revealed asophisticated molecular network regulating cardiac regeneration in the zebrafish and neonatal mouse heart. Here,we review both the classical and recent literature on the molecular and cellular mechanisms underlying heartregeneration, with a particular focus on how injury triggers the cell-cycle re-entry of quiescent cardiomyocytes toreplenish their massive loss after myocardial infarction or ventricular resection. We highlight several importantsignaling pathways for cardiomyocyte proliferation and propose a working model of how these injury-inducedsignals promote cardiomyocyte proliferation. Thus, this concise review provides up-to-date research progresses onheart regeneration for investigators in the field of regeneration biology.展开更多
Cardiac regeneration is an ancestral trait in vertebrates that is lost both as more recent vertebrate lineages evolved to adapt to new environments and selective pressures,and as members of certain species development...Cardiac regeneration is an ancestral trait in vertebrates that is lost both as more recent vertebrate lineages evolved to adapt to new environments and selective pressures,and as members of certain species developmentally progress towards their adult forms.While higher vertebrates like humans and rodents resolve cardiac injury with permanent fibrosis and loss of cardiac output as adults,neonates of these same species can fully regenerate heart structure and function after injury–as can adult lower vertebrates like many teleost fish and urodele amphibians.Recent research has elucidated several broad factors hypothesized to contribute to this loss of cardiac regenerative potential both evolutionarily and developmentally:an oxygen-rich environment,vertebrate thermogenesis,a complex adaptive immune system,and cancer risk trade-offs.In this review,we discuss the evidence for these hypotheses as well as the cellular participators and molecular regulators by which they act to govern heart regeneration in vertebrates.展开更多
Cardiovascular diseases are the leading cause of death worldwide. Cardiomyocytes are capable of coordinatedcontractions, which are mainly responsible for pumping blood. When cardiac stress occurs, cardiomyocytesunderg...Cardiovascular diseases are the leading cause of death worldwide. Cardiomyocytes are capable of coordinatedcontractions, which are mainly responsible for pumping blood. When cardiac stress occurs, cardiomyocytesundergo transition from physiological homeostasis to hypertrophic growth, proliferation, or apoptosis. During theseprocesses, many cellular factors and signaling pathways participate. PTEN is a ubiquitous dual-specificityphosphatase and functions by dephosphorylating target proteins or lipids, such as PIP3, a second messenger in thePI3K/AKT signaling pathway. Downregulation of PTEN expression or inhibiting its biologic activity improves heartfunction, promotes cardiomyocytes proliferation, reduces cardiac fibrosis as well as dilation, and inhibits apoptosisfollowing ischemic stress such as myocardial infarction. Inactivation of PTEN exhibits a potentially beneficialtherapeutic effects against cardiac diseases. In this review, we summarize various strategies for PTEN inactivationand highlight the roles of PTEN-less in regulating cardiomyocytes during cardiac development and stress responses.展开更多
基金Shaanxi Province Natural Science Foundation,China(Grant No.:2021JM-568).
文摘Hyaluronan and proteoglycan link protein 1(Hapln1)supports active cardiomyogenesis in zebrafish hearts,but its regulation in mammal cardiomyocytes is unclear.This study aimed to explore the potential regulation of Hapln1 in the dedifferentiation and proliferation of cardiomyocytes and its therapeutic value in myocardial infarction with human induced pluripotent stem cell(hiPSC)-derived cardiomyocytes(CMs)and an adult mouse model of myocardial infarction.HiPSC-CMs and adult mice with myocardial infarction were used as in vitro and in vivo models,respectively.Previous single-cell RNA sequencing data were retrieved for bioinformatic exploration.The results showed that recombinant human Hapln1(rhHapln1)promotes the proliferation of hiPSC-CMs in a dose-dependent manner.As a physical binding protein of Hapln1,versican interacted with Nodal growth differentiation factor(NODAL)and growth differentiation factor 11(GDF11).GDF11,but not NODAL,was expressed by hiPSC-CMs.GDF11 expression was unaffected by rhHapln1 treatment.However,this molecule was required for rhHapln1-mediated activation of the transforming growth factor(TGF)-β/Drosophila mothers against decapentaplegic protein(SMAD)2/3 signaling in hiPSC-CMs,which stimulates cell dedifferentiation and proliferation.Recombinant mouse Hapln1(rmHapln1)could induce cardiac regeneration in the adult mouse model of myocardial infarction.In addition,rmHapln1 induced hiPSC-CM proliferation.In conclusion,Hapln1 can stimulate the dedifferentiation and proliferation of iPSC-derived cardiomyocytes by promoting versican-based GDF11 trapping and subsequent activation of the TGF-β/SMAD2/3 signaling pathway.Hapln1 might be an effective hiPSC-CM dedifferentiation and proliferation agent and a potential reagent for repairing damaged hearts.
基金supported by National Natural Science Foundation of China(Grant No.81871244)Primary Research&Development Plan of Jiangsu Province(BE2019700,China)+4 种基金Jiangsu Province“333”project(BRA2018016,China)six talent peaks project in Jiangsu Province(2019-WSN-122,China)Projects of International Cooperation from Jiangsu(BX2019100,China)international cooperation and exchange from Zhenjiang(GJ2020010,China)key funds from health commission of jiangsu(ZD2021009,China)。
文摘Cardiac-resident macrophages(CRMs)play important roles in homeostasis,cardiac function,and remodeling.Although CRMs play critical roles in cardiac regeneration of neonatal mice,their roles are yet to be fully elucidated.Therefore,this study aimed to investigate the dynamic changes of CRMs during cardiac ontogeny and analyze the phenotypic and functional properties of CRMs in the promotion of cardiac regeneration.During mouse cardiac ontogeny,four CRM subsets exist successively:CX3CR1+CCR2-Ly6C-MHCII-(MP1),CX3CR1lowCCR2lowLy6C-MHCII-(MP2),CX3CR1-CCR2+Ly6C+MHCII-(MP3),and CX3CR1+CCR2-Ly6C-MHCII+(MP4).MP1 cluster has different derivations(yolk sac,fetal liver,and bone marrow)and multiple functions population.Embryonic and neonatal-derived-MP1 directly promoted cardiomyocyte proliferation through Jagged-1-Notch1 axis and significantly ameliorated cardiac injury following myocardial infarction.MP2/3 subsets could survive throughout adulthood.MP4,the main population in adult mouse hearts,contributed to inflammation.During ontogeny,MP1 can convert into MP4 triggered by changes in the cellular redox state.These findings delineate the evolutionary dynamics of CRMs under physiological conditions and found direct evidence that embryonic and neonatal-derived CRMs regulate cardiomyocyte proliferation.Our findings also shed light on cardiac repair following injury.
基金This research was supported by grants from the Ministry of Science and Technology of China(2018YFA0801004 and 2018YFA0800103)National Science Foundation of China(NSFC31530044 and NSFC31970780)We acknowledge Guozhen Wu for invaluable assistanee with fish care.We are grateful to Mark Mercola and members of TPZ laboratory for comments on the manuscript and helpful discussions.
文摘Heart regeneration occurs by dedifferentiation and proliferation of pre-existing cardiomyocytes(CMs).However,the signaling mechanisms by which injury induces CM renewal remain incompletely understood.Here,we find that cardiac injury in zebrafish induces expression of the secreted Wnt inhibitors,including Dickkopf 1(Dkkl),Dkk3,secreted Frizzled-related protein 1(sFrpl),and sFrp2,in cardiac tissue adjacent to injury sites.Experimental blocking of Wnt activity via Dkkl overexpression enhances CM proliferation and heart regeneration,whereas ectopic activation of Wnt8 signaling blunts injury-induced CM dedifferentiation and proliferation.Although Wnt signaling is dampened upon injury,the cytoplasmic β-catenin is unexpectedly increased at disarrayed CM sarcomeres in myocardial wound edges.Our analyses indicated that p21-activated kinase 2(Pak2)is induced at regenerating CMs,where it phosphorylates cytoplasmic β-catenin at Ser 675 and increases its stability at disassembled sarcomeres.Myocardial-specific induction of the phospho-mimeticβ-catenin(S675E)enhances CM dedifferentiation and sarcomere disassembly in response to injury.Conversely,inactivation of Pak2 kinase activity reduces the Ser 675-phosphorylatedβ-catenin(pS675-β-catenin)and attenuates CM sarcomere disorganization and dedifferentiation・Taken together,these findings demonstrate that coordination of Wnt signaling inhibition and Pak2/pS675-βYatenin signaling enhances zebrafish heart regeneration by supporting CM dedifferentiation and proliferation.
基金supported by the National Natural Science Foundation of China(No.82070314,81600244)the Natural Science Foundation of Shandong Province,China(No.ZR2021MC189).
文摘In the mammalian heart,cardiomyocytes are forced to withdraw from the cell cycle shortly after birth,limiting the ability of the heart to regenerate and repair.The development of multimodal regulation of cardiac proliferation has verified that pre-existing cardiomyocyte proliferation is an essential driver of cardiac renewal.With the continuous development of genetic lineage tracking technology,it has been revealed that cell cycle activity produces polyploid cardiomyocytes during the embryonic,juvenile,and adult stages of cardiogenesis,but newly formed mononucleated diploid cardiomyocytes also elevated sporadically during myocardial infarction.It implied that adult cardiomyocytes have a weak regenerative capacity under the condition of ischemia injury,which offers hope for the clinical treatment of myocardial infarction.However,the regeneration frequency and source of cardiomyocytes are still low,and the mechanism of regulating cardiomyocyte proliferation remains further explained.It is noteworthy to explore what force triggers endogenous cardiomyocyte proliferation and heart regeneration.Here,we focused on summarizing the recent research progress of emerging endogenous key modulators and crosstalk with other signaling pathways and furnished valuable insights into the internal mechanism of heart regeneration.In addition,myocardial transcription factors,non-coding RNAs,cyclins,and cell cycle-dependent kinases are involved in the multimodal regulation of pre-existing cardiomyocyte proliferation.Ultimately,awakening the myocardial proliferation endogenous modulator and regeneration pathways may be the final battlefield for the regenerative therapy of cardiovascular diseases.
基金supported by the grant to Chunyu Zeng from the National Key R&D Program of China(2022YFA1104500)the National Natural Science Foundation of China(82200307)the grant to Chunyu Zeng from the National Natural Science Foundation of China(81930008).
文摘The formation of new and functional cardiomyocytes requires a 3-step process:dedifferentiation,proliferation,and redifferentiation,but the critical genes required for efficient dedifferentiation,proliferation,and redifferentiation remain unknown.In our study,a circular trajectory using single-nucleus RNA sequencing of the pericentriolar material 1 positive(PCM1^(+))cardiomyocyte nuclei from hearts 1 and 3 days after surgery-induced myocardial infarction(MI)on postnatal Day 1 was reconstructed and demonstrated that actin remodeling contributed to the dedifferentiation,proliferation,and redifferentiation of cardiomyocytes after injury.We identified four top actin-remodeling regulators,namely Tmsb4x,Tmsb10,Dmd,and Ctnna3,which we collectively referred to as 2D2P.Transiently expressed changes of 2D2P,using a polycistronic non-integrating lentivirus driven by Tnnt2(cardiac-specific troponin T)promoters(Tnnt2-2D2P-NIL),efficiently induced transiently proliferative activation and actin remodeling in postnatal Day 7 cardiomyocytes and adult hearts.Furthermore,the intramyocardial delivery of Tnnt2-2D2P-NIL resulted in a sustained improvement in cardiac function without ventricular dilatation,thickened septum,or fatal arrhythmia for at least 4 months.In conclusion,this study highlights the importance of actin remodeling in cardiac regeneration and provides a foundation for new gene-cocktail-therapy approaches to improve cardiac repair and treat heart failure using a novel transient and cardiomyocyte-specific viral construct.
基金This paper was supported by grants from the National Key Research&Development Program of China(2018YFA080051)the National Natural Science Foundation of China(31730061 and 81870198).
文摘Heart regeneration is a fascinating and complex biological process. Decades of intensive studies have revealed asophisticated molecular network regulating cardiac regeneration in the zebrafish and neonatal mouse heart. Here,we review both the classical and recent literature on the molecular and cellular mechanisms underlying heartregeneration, with a particular focus on how injury triggers the cell-cycle re-entry of quiescent cardiomyocytes toreplenish their massive loss after myocardial infarction or ventricular resection. We highlight several importantsignaling pathways for cardiomyocyte proliferation and propose a working model of how these injury-inducedsignals promote cardiomyocyte proliferation. Thus, this concise review provides up-to-date research progresses onheart regeneration for investigators in the field of regeneration biology.
基金This research was made possible by NIH F31 Fellowship(S.C.),NIH(R01HL138456)Department of Defense(W81XWH1910206)Program for Breakthrough Biomedical Research,and UCSF Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research Seed Grant(G.N.H.).
文摘Cardiac regeneration is an ancestral trait in vertebrates that is lost both as more recent vertebrate lineages evolved to adapt to new environments and selective pressures,and as members of certain species developmentally progress towards their adult forms.While higher vertebrates like humans and rodents resolve cardiac injury with permanent fibrosis and loss of cardiac output as adults,neonates of these same species can fully regenerate heart structure and function after injury–as can adult lower vertebrates like many teleost fish and urodele amphibians.Recent research has elucidated several broad factors hypothesized to contribute to this loss of cardiac regenerative potential both evolutionarily and developmentally:an oxygen-rich environment,vertebrate thermogenesis,a complex adaptive immune system,and cancer risk trade-offs.In this review,we discuss the evidence for these hypotheses as well as the cellular participators and molecular regulators by which they act to govern heart regeneration in vertebrates.
基金This work is supported by National Natural Science Foundation of China(Nos.81670257,81970227 to J.Chen,and 82000244 to F.Gao)Zhejiang Provincial NSF project(LZ20H020001 to J.Chen.)China Postdoctoral Science Foundation(2020 M671751 and 2021 T140596 to F.Gao).
文摘Cardiovascular diseases are the leading cause of death worldwide. Cardiomyocytes are capable of coordinatedcontractions, which are mainly responsible for pumping blood. When cardiac stress occurs, cardiomyocytesundergo transition from physiological homeostasis to hypertrophic growth, proliferation, or apoptosis. During theseprocesses, many cellular factors and signaling pathways participate. PTEN is a ubiquitous dual-specificityphosphatase and functions by dephosphorylating target proteins or lipids, such as PIP3, a second messenger in thePI3K/AKT signaling pathway. Downregulation of PTEN expression or inhibiting its biologic activity improves heartfunction, promotes cardiomyocytes proliferation, reduces cardiac fibrosis as well as dilation, and inhibits apoptosisfollowing ischemic stress such as myocardial infarction. Inactivation of PTEN exhibits a potentially beneficialtherapeutic effects against cardiac diseases. In this review, we summarize various strategies for PTEN inactivationand highlight the roles of PTEN-less in regulating cardiomyocytes during cardiac development and stress responses.